PROJECT SUMMARY/ABSTRACT Alzheimer?s disease (AD) is a progressive multifactorial disease affecting more than 50 million people worldwide, and is the most common dementia of late-life. To date, no interventions have demonstrated substantial therapeutic efficacy to prevent, delay or treat AD. In recent years, both cardiovascular disorders (CVD) and genetic factors (ApoE4) have been attributed to an increased risk of developing AD. The pathological arm of the Renin Angiotensin System (RAS) has been implicated in both CVD and AD, whereas the protective arm, including Angiotensin (1-7)[A(1-7)], Mas receptor and ACE2 are known to counter-regulate these effects. A(1- 7), through the Mas receptor, is known to reduce inflammation and oxidative (OS) in several disease states and it also has regenerative effects by upregulating endogenous stem cell populations. Data from clinical studies have shown that both A(1-7) and ACE2 are reduced in AD patients and several in-vivo studies support the efficacy of A(1-7) in treating AD. While the effects of A(1-7) in AD models have been extremely promising, its short half-life and lack of oral bioavailability make it challenging to develop as a therapeutic modality. In order to overcome this shortcoming, our lab has developed an equipotent small molecule analogues of A(1-7), RASRx1902 and RASRx1911. RASRx1902 and RASRx1911 have been shown to reduce inflammation and OS in target organs as well as having a regenerative effect on damaged tissues. A recent study from our lab showed that RASRx1902 and RASRx1911 were able to improve cognitive function as well as reduce OS in the brain in a mouse model of hypertension induced cognitive dysfunction (transverse aortic constriction [TAC]). Since Mas agonism is known to have a beneficial effect in AD, we hypothesize that these molecules can be developed as a potential new therapeutic for the treatment of AD and related dementias. The primary objective of this proposal are to advance development of one small molecule Mas agonist to submission of an Investigation New Drug Application (IND) for the treatment of AD and related dementias through: 1. Evaluation of the oral efficacy of RASRx1902 and RASRx1911 in TAC and AD mouse models (5xFAD & ApoE4); 2. Assessment of the efficacy of RASRx1902 in TAC-ApoE4 mice, 3. Scale up of one Mas agonist manufactured under Good Manufacturing Practices (GMP); 4. Development of a formulation of one Mas agonist for Phase I clinical trial; 5. Completion of ADME, (PK) and IND-enabling Toxicology studies; 6. Preparation Pre IND and IND Documentation; 7. Conduct of a Pre IND meeting; and 8. Filing of an IND. Research proposed herein is responsive to PAS 18-820 to develop and evaluate therapies ?that prevent Alzheimer's disease (AD), slow its progression or treat its cognitive and behavioral symptoms?.